There is a paucity of data on long-term results of dietary treatment for obesity. Diets emphasizing fat restriction, low carbohydrate or high protein intake are each promoted in popular books, but with little evidence to support one over the other for their short- or long-term use. The aims of the proposed research are to test the effectiveness for weight loss and weight maintenance of 4 diets differing in macronutrient composition: moderate in fat (35% energy) with two different protein levels (15% and 25%), and low in fat (20% energy), also with 15% and 25% protein. The moderate-fat diet will be patterned after a Mediterranean diet. All 4 dietary approaches will be low in saturated fat, and will involve reduction in total energy intake. All participants will receive a state-of-the-art behavioral therapy program standardized across the two centers. We will test the hypothesis that higher baseline insulin, RQ and VO2max will be associated with smaller weight loss and more difficulty maintaining the weight loss during maintenance. Dietary satisfaction and satiety will be assessed as potential predictors of success. 400 men and 400 women, BMI 27-39 kg/m2, will be randomized among the 4 dietary treatments. Each diet will be developed to be practical and suitable for public health recommendations, and would be expected to have a favorable effect on cardiovascular risk factors. The primary outcome variable will be change in total body weight from baseline to 2 years. Secondary outcomes related to obesity are total body fat, visceral fat mass, BMI, and waist and hip circumferences. Other outcomes include blood pressure, fasting blood lipids, apolipoproteins, insulin, glucose, and hemoglobin A1C. The results will be straightforwardly applicable to public health and clinical guidelines for obesity, and will increase our understanding of the biology of obesity and weight loss.